ClinVar Miner

Submissions for variant NM_002234.4(KCNA5):c.926G>A (p.Gly309Asp)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001057633 SCV001222136 uncertain significance Atrial fibrillation, familial, 7 2020-07-25 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 309 of the KCNA5 protein (p.Gly309Asp). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs369120527, ExAC 0.009%). This variant has not been reported in the literature in individuals with KCNA5-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV001057633 SCV001268554 uncertain significance Atrial fibrillation, familial, 7 2018-03-16 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354757 SCV001549449 uncertain significance not provided no assertion criteria provided clinical testing The KCNA5 p.Gly309Asp variant was identified in 1 of 614 proband chromosomes (frequency: 0.00163) from individuals with lone atrial fibrillation but was not found to affect the subcellular localization of the Kv1.5 potassium channel subunit encoded by the KCNA5 gene (Christophersen_2012_PMID:23264583). The variant was identified in dbSNP (ID: rs369120527) but was not identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in control databases in 19 of 278892 chromosomes at a frequency of 0.000068 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 17 of 126286 chromosomes (freq: 0.000135), European (Finnish) in 1 of 24770 chromosomes (freq: 0.00004) and Latino in 1 of 35364 chromosomes (freq: 0.000028), but was not observed in the African, Ashkenazi Jewish, East Asian, Other or South Asian populations. The p.Gly309 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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